Cabazitaxel is the active ingredient in the product JEVTANA® Injection 60 mg/1.5 mL, sold by Sanofi Aventis as a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution in single-use vials containing 60 mg cabazitaxel (calculated on an anhydrous and solvent free basis) and 1.56 g of polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. JEVTANA® Injection is a micellar formulation.
Cabazitaxel shows polymorphism and the polymorphic form A of an acetone solvate is known to offer manufacturing feasibility, reproducibility, and stability as reported in art.
The JEVTANA® product requires two dilutions prior to intravenous infusion. The first dilution produces a composition of approximately 4.5 mL clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water. This pre-mix solution is supersaturated by about 400% (10 mg cabazitaxel/mL) is inherently physically unstable. It requires repeated inversions for at least 45 seconds to assure complete mixing of the concentrated drug solution and the diluent. The pre-mix solution must be used immediately and requires further dilution before administration. A volume of premix solution calculated based on a dose of 25 mg/m2 is withdrawn and injected into a PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. After this second dilution, the concentration of cabazitaxel in the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL. The diluted infusion solution should be used for intravenous administration immediately, within 8 hours, if stored at room temperature, or within 24 hours, if stored under refrigerated conditions, including the 1-hour infusion period. Because of the serial dilutions required, there is a chance that an incorrect final dosage form will be prepared. Severe complications can result from overdose, which may include exacerbation of the adverse reactions, sometimes leading to fatal outcomes. The most common serious adverse events with cabazitaxel chemotherapy included myelosuppression (i.e., anaemia, neutropenia, leukopenia, and thrombocytopenia), hypersensitivity reactions, fatigue, diarrhea, peripheral neuropathy, back pain, and arthralgia and also potential GI symptoms, such as nausea, vomiting, and diarrhea and renal failure.
JEVTANA® (cabazitaxel injection 60 mg/1.5 mL) comprises of polysorbate 80 as a primary solubilizing vehicle. However, based on the published literature, polysorbate 80 is known to induce hypersensitivity reactions.
Apart from the reconstitution errors associated with JEVTANA® causing exacerbation of adverse events, this two-step dilution process is cumbersome and time consuming. In addition, complications like drug crystallization and possibilities of needle stick injuries and contamination during dilution are also concerns. As both the pre-mix solution and the second diluted infusion solution are supersaturated, the solutions may crystallize over time. If crystals and/or particulates appear in the diluted infusion solution, the formulation is ruined, may not be used, and must be thrown away.
There remains a need for improved formulations of cabazitaxel having improved ease of manufacture, means of administration, and stability over time. There remains a need for formulations which are easy for healthcare providers to prepare and administer. There remains a need for cabazitaxel formulation having improved stability over time, especially when stored under ambient conditions.
It is an object of the invention to provide stabilized, ready-to-dilute, cabazitaxel formulations.
It is another object of the invention to provide stabilized, ready-to-use, cabazitaxel formulations.
It is another object of the invention to provide a process for preparing stabilized, ready-to-dilute, cabazitaxel formulations.
It is another object of the invention to provide a process for preparing stabilized, ready-to-use, cabazitaxel formulations.
It is another object of the present invention to provide safe, efficacious and easy to use formulations of cabazitaxel.
It is another object of the present invention to provide methods for treating patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen in combination with prednisone by administering stable ready-to-dilute/ready-to-use parenteral formulations of cabazitaxel.